Compounds and methods of preparing compounds s1p1 modulators

ABSTRACT

The present embodiments are directed, in part, to processes and compositions that can, for example, be used in the preparation compounds of Formula (I), or a pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 62/937,485, filed Nov. 19, 2019, which is hereby incorporated byreference in its entirety.

FIELD

Embodiments disclosed herein are directed to compounds and methods ofpreparing compounds, or pharmaceutically acceptable salts thereof, thatcan, for example, be used for modulating S1P1 receptor activity.

BACKGROUND

Compounds of

are reported in International Application Publication No. WO2018/231745, which is hereby incorporated by reference in its entirety.In addition to the methods of making such compounds, or pharmaceuticallyacceptable salts thereof, others methods of synthesis may still beneeded. The present disclosure fulfills these needs and others.

SUMMARY OF EMBODIMENTS

In some embodiments, methods of preparing compounds of Formula (I), or apharmaceutically acceptable salt thereof are provided. In someembodiments, the methods comprise contacting

under suitable conditions to produce the compound having the structureof

wherein A, B, E, X, Y, R₁, R₂, R₃, R₄, and R₅ are as provided for hereinand, for example, can be selected from the respective groups of chemicalmoieties described herein.

In some embodies, the methods comprise:

(a) adding a coupling reagent and optionally an additive to a solutionof a compound of

in a first organic solvent to form a mixture and stirring the mixturefor at least about 5 minutes;

(b) stirring the mixture of step (a) with a compound of

-   -   (c) heating the mixture of step (b) to a temperature of at least        about 40° C. and stirring the mixture under the temperature;

(d) cooling the mixture of step (c) and adding water to the mixture toform a slurry;

(e) stirring the slurry of step (d);

(f) filtering the slurry of step (e) to obtain a solid;

(g) washing the solid of the step (f) with water and/or a second organicsolvent; and

(h) drying the solid of the step (g) at a temperature of at least about30° C. under vacuum to form the compound of

wherein the variables are provided herein.

In some embodiments, also provided are processes of preparing compoundsof Formula (I), or a pharmaceutically acceptable salt thereof comprisingthe steps of:

-   -   (a) adding EDC hydrochloride and ethyl cyanohydroxyiminoacetate        to a solution of a compound of

-   -    in dimethylformamide to form a mixture and stirring the mixture        for at least about 1 hour;    -   (b) stirring the mixture of the step (a) with a compound of

-   -    Formula (III);    -   (c) heating the mixture of the step (b) to a temperature at        about 95° C. and stirring the mixture under the temperature for        at least about 5 hour;    -   (d) cooling the mixture of the step (c) to about 15-20° C. and        adding water to form a slurry;    -   (e) stirring the slurry of the step (d) at about 15-20° C. for        about 1 h;    -   (f) filtering the slurry of the step (e) to from a solid;    -   (g) washing the solid of the step (f) with water and        methyl-tert-butyl ether; and

(h) drying the solid of the step (g) at about 55° C. under vacuum toform the compound of

wherein the variables are as defined herein.

In some embodiments, also provided are processes of preparing thecompound having the structure of

or a pharmaceutically acceptable salt thereof comprising the steps of:

-   -   (a) adding EDC hydrochloride and ethyl cyanohydroxyiminoacetate        to a solution of

-   -    in dimethylformamide to form a mixture and stirring the mixture        for at least about 1 hour;    -   (b) stirring the mixture of the step (a) with

-   -    for about 1 hour;    -   (c) heating the mixture of the step (b) to a temperature at        about 95° C. and stirring the mixture under the temperature for        at least about 5 hour;    -   (d) cooling the mixture of the step (c) to about 15-20° C. and        adding water to the mixture form a slurry;    -   (e) stirring the slurry of the step (d) at about 15-20° C. for        about 1 h;    -   (f) filtering the slurry of the step (e) to from a solid;    -   (g) washing the solid of the step (f) with water and        methyl-tert-butyl ether; and    -   (h) drying the solid of the step (g) at least about 55° C. under        vacuum to form

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof furthercomprising a method of preparing a compound of

comprising contacting

with R₂R₃C═O under suitable conditions, wherein the variables are asdefined herein.

In some embodiments, also provided are methods of preparing compounds of

comprising the steps of:

-   -   (a) adding pyrrolidine to a solution of a compound of

-   -    in a compound of R₂R₃C═O to form a mixture;    -   (b) heating the mixture of step (a) to reflux, stirring the        mixture for about 19.5 hours under the temperature, cooling the        mixture to about 15-20° C., and adding water to the mixture;    -   (c) adjusting the pH of the mixture of step (b) to about 2 with        HCl;    -   (d) stirring the mixture of step (c) with n-heptane to form a        slurry and stirring the slurry at about 15-20° C. for about 1        hour, and filtering the slurry to form a solid; and    -   (e) washing the solid of step (d) with water and n-heptane; and    -   (g) drying the solid of step (e) at about 50° C. under vacuum to        form the compound of

-   -    wherein:

A, B, and E are each independently N or CR₆;

X and Y are each independently O, S, or NR₇,

R₂, R₃, R₄, R₅, R₆, and R₇, are each independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl,or optionally substituted cycloheteroalkyl; R₂ and R₃ are togetheroptionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl; or R₄ and R₅ are together optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof furthercomprising methods of preparing a compound of

comprising contacting a compound of a formula of R₁CN with ammoniumhydroxide and wherein R₁ is H, OH, NH₂, NO₂, optionally substitutedcarbocycle, optionally substituted aryl group, optionally substitutedheteroaryl group, branched or unbranched alkyl alcohol, halo, branchedor unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl,nitrite, or alkylsulfanyl.

In some embodiments, also provided are methods of preparing a compoundof

comprising the steps of:

-   -   (a) adding hydroxylamine to a solution of a compound of R₁CN in        an alcohol form a mixture;    -   (b) heating the mixture of the step (a) to a temperature of        about 75° C. and stirring the mixture for about 4 hours under        the temperature to form a slurry    -   (c) cooling the slurry of the step (b) to ambient temperature        and stirring for about 16 hours under the ambient temperature;    -   (d) filtering the slurry of the step (c) to form a solid; and    -   (e) washing the solid of the step (d) with the alcohol and        drying the washed solid at about 50° C. under vacuum to form the        compound of

-   -    R₁ is as defined herein.

In some embodiments, provided are methods of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of

is contacted with the coupling reagent, with or without the addictive,to form an intermediate having the structure of

wherein R₈ is optionally substituted C1-C6 alkyl and R₂, R₃, R₄, R₅, R₆,and R₇, are as defined herein. In some embodiments, the intermediate ofFormula (XIII) is a compound having the structure of

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theintermediate having the structure of

further contacts the compound of

to form an intermediate having a structure of

wherein the variables are as defined herein. In some embodiments, theintermediate of Formula (XVI) is a compound having the structure of

In some embodiments, a compound of

or a pharmaceutically acceptable salt thereof, wherein R₈ is optionallysubstituted C1-C6 alkyl and R₂, R₃, R₄, R₅, R₆, and R₇, are as definedherein, is provided. In some embodiments, a compound having thestructure of

or a pharmaceutically acceptable salt thereof is provided.

In some embodiments, a compound having the structure of

or a pharmaceutically acceptable salt thereof is provided, wherein thevariables are as defined herein. In some embodiments, a compound havingthe structure of

or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of forming a compound of Formula I, themethod comprising reacting the compound having the formula of

under thermal cyclodehydration conditions to form a compound of

In some embodiments, a crystalline form of the compound having theformula

is provided. In some embodiments, the crystalline form is Form I.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: High performance liquid chromatography (HPLC) chromatogram ofN-hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2)

FIG. 2: High performance liquid chromatography (HPLC) chromatogram of2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid(Compound 4-2).

FIG. 3: High performance liquid chromatography (HPLC) chromatogram of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1).

FIG. 4: Polarized Light Microscopy (PLM) analysis result of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1) (10 m Scale).

FIG. 5: Differential thermal analysis (DSC) result of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1).

FIG. 6: X-ray powder diffraction (XRPD) results of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1).

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms have thesame meaning as is commonly understood by one of ordinary skill in theart to which the embodiments disclosed belongs. In the event that thereis a plurality of definitions for terms cited herein, those in thissection prevail unless otherwise stated. All patents, applications,published applications, and other publications cited herein areincorporated by reference in their entirety.

As used herein, the terms “a” or “an” means that “at least one” or “oneor more” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “additive” or “coupling additive” means areagent that is suitable in combination with a coupling reagent incoupling reactions to inhibit side reactions and reduce or eliminateracemization. In some embodiments, an additive is, but not limited to,ethyl cyanohydroxyiminoacetate, N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene2,3-dicarboximide (HONB), 1-hydroxybenzotriazole(HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt),1-hydroxy-7-azabenzotriazole (HOAt) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), aza derivativeof 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhat),4-(N,N-Dimethylamino)pyridine) (DMAP), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), or any combinationsthereof.

As used herein, the term “alcohol” means any organic compound in which ahydroxyl group (—OH) is bound to a carbon atom, which in turn is boundto other hydrogen and/or carbon atoms. For example, the term “alcohol”means a straight or branched alkyl-OH group of 1 to 20 carbon atoms,including, but not limited to, methanol, ethanol, n-propanol,isopropanol, t-butanol, and the like. In some embodiments, the alkyl-OHchain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atomsin length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atomsin length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atomsin length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbonatoms in length.

As used herein, the terms “alkoxy”, “phenyloxy”, “benzoxy” and“pyrimidinyloxy” refer to an alkyl group, phenyl group, benzyl group, orpyrimidinyl group, respectively, each optionally substituted, that isbonded through an oxygen atom. For example, the term “alkoxy” means astraight or branched —O-alkyl group of 1 to 20 carbon atoms, including,but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy,and the like. In some embodiments, the alkoxy chain is from 1 to 10carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the term “alkyl” means a saturated hydrocarbon groupwhich is straight-chained or branched. An alkyl group can contain from 1to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2or 3 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl),butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl,isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl,2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and thelike.

As used herein, the term “alkylene” or “alkylenyl” means a divalentalkyl linking group. An example of an alkylene (or alkylenyl) ismethylene or methylenyl (—CH2-).

As used herein, the term “alkynyl” means a straight or branched alkylgroup having one or more triple carbon-carbon bonds and 2-20 carbonatoms, including, but not limited to, acetylene, 1-propylene,2-propylene, and the like. In some embodiments, the alkynyl chain is 2to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the terms “ambient temperature” and “room temperature”or “RT”, as used herein, are understood in the art, and refer generallyto a temperature, e.g. a reaction temperature, that is about thetemperature of the room in which the reaction is carried out, forexample, a temperature from about 20° C. to about 30° C., such as at orabout 25° C.

As used herein, the term “amide” means to a functional group containinga carbonyl group linked to a nitrogen atom or any compound containingthe amide functional group. For example, amides are derived fromcarboxylic acid and an amine.

As used herein, the term “aryl” means a monocyclic, bicyclic, orpolycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons.In some embodiments, aryl groups have from 6 to 20 carbon atoms or from6 to 10 carbon atoms. Examples of aryl groups include, but are notlimited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,indenyl, tetrahydronaphthyl, and the like. Examples of aryl groupsinclude, but are not limited to:

As used herein, the term “carbocycle” means a 5-6, or 7-membered,saturated or unsaturated cyclic ring, optionally containing, S, or Natoms as part of the ring. Examples of carbocycles include, but are notlimited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, andany of the heterocycles recited above.

As used herein, the term, “compound” means all stereoisomers, tautomers,and isotopes of the compounds described herein.

As used herein, the terms “comprising” (and any form of comprising, suchas “comprise”, “comprises”, and “comprised”), “having” (and any form ofhaving, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”), or “containing” (and anyform of containing, such as “contains” and “contain”), are inclusive oropen-ended and do not exclude additional, unrecited elements or methodsteps.

As used herein, the term “contacting” means bringing together of twocompounds/atoms to form at least one covalent bond between the compoundsor atoms.

As used herein, the term “coupling reagent” or “peptide couplingreagent” means a reagent that facilitate to form an amide bond betweenan amine and carboxylic acid including but not limited to carbodiimides,aminium/uronium and phosphonium salts, and propanephosphonic acidanhydride. For example, the coupling reagent is diisopropylcarbodiimide(DIC), dicyclohexylcarbodiimide (DCC),1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, Hexafluorophosphate AzabenzotriazoleTetramethyl Uronium (HATU),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU),O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatO-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HCTU),Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyAOP), Propanephosphonic acid anhydride (PPAA,T3P), or any combination thereof.

As used herein, the term “cyano” means —CN.

As used herein, the term “cycloalkyl” means non-aromatic cyclichydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups thatcontain up to 20 ring-forming carbon atoms. Cycloalkyl groups caninclude mono- or polycyclic ring systems such as fused ring systems,bridged ring systems, and spiro ring systems. In some embodiments,polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkylgroup can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6,from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(having a bond in common with) to the cycloalkyl ring, for example,benzo or thienyl derivatives of pentane, pentene, hexane, and the like(e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).

As used herein, the term “cycloheteroalkyl” means as used herein aloneor as part of another group refers to a 5-, 6- or 7-membered saturatedor partially unsaturated ring which includes 1 to 2 hetero atoms such asnitrogen, oxygen and/or sulfur, linked through a carbon atom or aheteroatom, where possible, optionally via the linker (CH₂)n (where n is0, 1, 2 or 3). The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of the substituents for alkyl or aryl setout herein. In addition, any of the cycloheteroalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

As used herein, the terms “for example” and “such as,” and grammaticalequivalences thereof.

As used herein, the term “halo” means halogen groups including, but notlimited to fluoro, chloro, bromo, and iodo.

As used herein, the term “haloalkoxy” means an —O-haloalkyl group. Anexample of an haloalkoxy group is OCF₃.

As used herein, the term “haloalkyl” means a C₁₋₆alkyl group having oneor more halogen substituents. Examples of haloalkyl groups include, butare not limited to, CF₃, C₂F₅, CH₂F, CHF₂, CCl₃, CHCl₂, CH₂CF₃, and thelike.

As used herein, the term “heteroaryl” means an aromatic heterocyclehaving up to 20 ring-forming atoms (e.g., C) and having at least oneheteroatom ring member (ring-forming atom) such as sulfur, oxygen, ornitrogen. In some embodiments, the heteroaryl group has at least one ormore heteroatom ring-forming atoms, each of which are, independently,sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl grouphas from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms,from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms. Insome embodiments, the heteroaryl group contains 2 to 14 carbon atoms,from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments,the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic(e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroarylgroups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrroyl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl,oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, indolizinyl,isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl,phenoxazinyl groups, and the like. Suitable heteroaryl groups include1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole,oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine,and 2-aminopyridine.

As used herein, the term “heterocycle” or “heterocyclic ring” means a 5-to 7-membered mono- or bicyclic or 7- to 10-membered bicyclicheterocyclic ring system any ring of which may be saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms chosen from N, O and S, and wherein the N and S heteroatomsmay optionally be oxidized, and the N heteroatom may optionally bequaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring.Particularly useful are rings containing one oxygen or sulfur, one tothree nitrogen atoms, or one oxygen or sulfur combined with one or twonitrogen atoms. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of heterocyclic groups include, but are not limited to,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same asmorpholinyl.

As used herein, the term “heterocycloalkyl” means non-aromaticheterocycles having up to 20 ring-forming atoms including cyclizedalkyl, alkenyl, and alkynyl groups, where one or more of thering-forming carbon atoms is replaced by a heteroatom such as an O, N,or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g.,fused, bridged, or spiro systems). In some embodiments, theheterocycloalkyl group has from 1 to 20 carbon atoms, or from 3 to 20carbon atoms. In some embodiments, the heterocycloalkyl group contains 3to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 triplebonds. Examples of heterocycloalkyl groups include, but are not limitedto, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole,benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl,oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl,imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. In addition,ring-forming carbon atoms and heteroatoms of a heterocycloalkyl groupcan be optionally substituted by oxo or sulfido. For example, aring-forming S atom can be substituted by 1 or 2 oxo (form a S(O) orS(O)₂). For another example, a ring-forming C atom can be substituted byoxo (form carbonyl). Also included in the definition of heterocycloalkylare moieties that have one or more aromatic rings fused (having a bondin common with) to the nonaromatic heterocyclic ring including, but notlimited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, andbenzo derivatives of heterocycles such as indolene, isoindolene,4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl,and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbonatoms and heteroatoms of the heterocycloalkyl group can be optionallysubstituted by oxo or sulfido.

As used herein, the term “heterocycloalkylalkyl” means a C₁₋₆ alkylsubstituted by heterocycloalkyl.

As used herein, the term “hydroxy” or “hydroxyl” means an —OH group.

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” means analkyl group substituted by a hydroxyl group. Examples of a hydroxylalkylinclude, but are not limited to, —CH₂OH and —CH₂CH₂OH.

As used herein, the term “patient,” means any animal, including mammals,such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle,sheep, horses, or primates, such as humans.

As used herein, the term “isolating” means that separating the compoundsdescribed herein from other components of a synthetic organic chemicalreaction mixture by conventional techniques, such as filtration.

As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat,or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or ahuman. In some embodiments, the mammal is a human.

As used herein, the term “nitro” means —NO₂.

As used herein, the term “n-membered”, where n is an integer, typicallydescribes the number of ring-forming atoms in a moiety, where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl ring.

As used herein, the phrase “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent groups, provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group is optionally substituted, then 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, the phrase “pharmaceutically acceptable” means thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals. In some embodiments,“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

In some embodiments, the salt of a compound described herein is apharmaceutically acceptable salt thereof. As used herein, the phrase“pharmaceutically acceptable salt(s),” includes, but is not limited to,salts of acidic or basic groups. Compounds that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. Acids that may be used to prepare pharmaceuticallyacceptable acid addition salts of such basic compounds are those thatform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions including, but not limited to,sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite,phosphate, acid phosphate, isonicotinate, borate, acetate, lactate,salicylate, citrate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate,napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, andpamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds that include an amino moiety may form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include, but are not limited to, alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,ammonium, sodium, lithium, zinc, potassium, and iron salts. The presentembodiments also includes quaternary ammonium salts of the compoundsdescribed herein, where the compounds have one or more tertiary aminemoiety.

As used herein, the term “phenyl” means —C₆H₅. A phenyl group can beunsubstituted or substituted with one, two, or three suitablesubstituents.

As used herein, the term “purified” means that when isolated, theisolate contains at least 90%, at least 95%, at least 98%, or at least99% of a compound described herein by weight of the isolate.

As used herein, the phrase “quaternary ammonium salts” means derivativesof the disclosed compounds with one or more tertiary amine moietieswherein at least one of the tertiary amine moieties in the parentcompound is modified by converting the tertiary amine moiety to aquaternary ammonium cation via alkylation (and the cations are balancedby anions such as Cl⁻, CH₃COO⁻, and CF₃COO⁻), for example methylation orethylation.

As used herein, the term “solution/suspension” means a liquidcomposition wherein a first portion of the active agent is present insolution and a second portion of the active agent is present inparticulate form, in suspension in a liquid matrix.

As used herein, the term “solvent” means a usually liquid substancecapable of dissolving or dispersing one or more other substancesincluding water, inorganic nonaqueous solvent, and organic solvents. Theterm “inorganic nonaqueous solvent” means a solvent other than water,that is not an organic compound. Examples of the “inorganic nonaqueoussolvent” include, but are not limited to: liquid ammonia, liquid sulfurdioxide, sulfuryl chloride and sulfuryl chloride fluoride, phosphorylchloride, dinitrogen tetroxide, antimony trichloride, brominepentafluoride, hydrogen fluoride, pure sulfuric acid and other inorganicacids. The term “organic solvent” means carbon-based solvent. Examplesof the “organic solvent” include, but are not limited to: aromaticcompounds, e.g, benzene and toluene. alcohols, e.g, methanol, ethanol,and propanol, esters and ethers. ketones, e.g, acetone. amines. nitratedand halogenated hydrocarbons. The “organic solvent” includes both polarand non-polar organic solvent. The “polar organic solvent” means anorganic solvent that has large dipole moments (aka “partial charges”)and in general the organic solvent with dielectric constants greaterthan about 5 is considered as “polar organic solvent” while those withdielectric constants less than 5 are considered “non-polar organicsolvent.” Examples of the “polar organic solvent” include, but are notlimited to, acetic acid, methanol, acetone, and acetonitrile, DMSO, andDMF. Examples of the non-polar organic solvent include, but are notlimited to, benzene, carbon tetrachloride, and n-hexane. The “organicsolvent” includes both protonic and non-protonic organic solvent. Theterm “protonic organic solvent” means an organic solvent having ahydrogen atom bonded to oxygen or nitrogen (an acidic hydrogen atom).Examples of the “protonic organic solvent” include, but are not limitedto, methanol, ethanol, propanol, isopropanol, butanol, hexanol, phenol,acetic acid, benzoic acid and partly fluorinated compounds thereof.Examples of the “non-protonic organic solvent” include, but are notlimited to: ethylene glycol dimethyl ether, ethylene glycol methylethylether, diethylene glycol dimethyl ether, diethylene glycol methyl ethylether, triethylene glycol dimethyl ether, tetraethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol diethyl ether,1,3-dimethoxypropane, 1,2-dimethoxypropane, propylene glycol dimethylether, dipropylene glycol dimethyl ether, dioxane, dimethyl carbonate,ethyl methyl carbonate, diethyl carbonate, ethylene carbonate, propylenecarbonate, 2,3-dimethylethylene carbonate, butylene carbonate,acetonitrile, methoxy acetonitrile, propionitrile, butyrolactone,valerolactone, dimethoxyethane, sulforane, methylsulforane, sulfolene,dimethyl sulfone, ethylmethyl sulfone, and isopropyl methyl sulfone.

As used herein, the phrase “substantially isolated” means a compoundthat is at least partially or substantially separated from theenvironment in which it is formed or detected.

As used herein, the phrase “suitable substituent” or “substituent” meansa group that does not nullify the synthetic or pharmaceutical utility ofthe compounds described herein or the intermediates useful for preparingthem. Examples of suitable substituents include, but are not limited to:C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₅-C₆aryl, C₁-C₆alkoxy,C3-C₅heteroaryl, C₃-C₆cycloalkyl, C₅-C₆aryloxy, —CN, —OH, oxo, halo,haloalkyl, —NO₂, —CO₂H, —NH₂, —NH(C₁-C₈alkyl), —N(C₁-C₈alkyl)₂,—NH(C₆aryl), —N(C₅-C₆aryl)₂, —CHO, —CO(C₁-C₆alkyl), —CO((C₅-C₆)aryl),—CO₂((C₁-C₆)alkyl), and —CO₂((C₅-C₆)aryl). One of skill in art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compounds describedherein.

As used herein, the term “and without limitation” is understood tofollow unless explicitly stated otherwise.

At various places in the present specification, substituents ofcompounds may be disclosed in groups or in ranges. It is specificallyintended that embodiments include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁-C₆ alkyl” is specifically intended to individually disclosemethyl, ethyl, propyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds in which a variable appears more than once, each variablecan be a different moiety selected from the Markush group defining thevariable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound, the two Rgroups can represent different moieties selected from the Markush groupsdefined for R. In another example, when an optionally multiplesubstituent is designated in the form, for example,

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence. In theabove example, where the variable T¹ is defined to include hydrogens,such as when T¹ is CH₂, NH, etc., any H can be replaced with asubstituent.

It is further appreciated that certain features described herein, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features which are, for brevity, described in the context of asingle embodiment, can also be provided separately or in any suitablesubcombination.

It is understood that the present embodiments encompasses the process,where applicable, of stereoisomers, diastereomers and opticalstereoisomers of the compounds, as well as mixtures thereof.Additionally, it is understood that stereoisomers, diastereomers, andoptical stereoisomers of the compounds, and mixtures thereof, are withinthe scope of the embodiments. By way of non-limiting example, themixture may be a racemate or the mixture may comprise unequalproportions of one particular stereoisomer over the other. Additionally,the compounds can be provided as a substantially pure stereoisomers,diastereomers and optical stereoisomers (such as epimers).

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended to be included within the scope of theembodiments unless otherwise indicated. Compounds that containasymmetrically substituted carbon atoms can be isolated in opticallyactive or racemic forms. Methods of preparation of optically activeforms from optically active starting materials are known in the art,such as by resolution of racemic mixtures or by stereoselectivesynthesis. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are provided herein. Cis and trans geometric isomers ofthe compounds are also included within the present embodiments and canbe isolated as a mixture of isomers or as separated isomeric forms.Where a compound capable of stereoisomerism or geometric isomerism isdesignated in its structure or name without reference to specific R/S orcis/trans configurations, it is intended that all such isomers arecontemplated.

In some embodiments, the composition comprises a compound, or apharmaceutically acceptable salt thereof, that is at least 90%, at least95%, at least 98%, or at least 99%, or 100% enantiomeric pure, whichmeans that the ratio of one enantiomer to the other in the compositionis at least 90:1 at least 95:1, at least 98:1, or at least 99:1, or iscompletely in the form of one enantiomer over the other.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art, including, for example, chiral HPLC,fractional recrystallization using a chiral resolving acid which is anoptically active, salt-forming organic acid. Suitable resolving agentsfor fractional recrystallization methods include, but are not limitedto, optically active acids, such as the D and L forms of tartaric acid,diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid, and the various optically active camphorsulfonicacids such as β-camphorsulfonic acid. Other resolving agents suitablefor fractional crystallization methods include, but are not limited to,stereoisomerically pure forms of α-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent compositions can be determined by one skilled in theart.

Compounds may also include tautomeric forms. Tautomeric forms resultfrom the swapping of a single bond with an adjacent double bond togetherwith the concomitant migration of a proton. Tautomeric forms includeprototropic tautomers which are isomeric protonation states having thesame empirical formula and total charge. Examples of prototropictautomers include, but are not limited to, ketone-enol pairs,amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs,enamine-imine pairs, and annular forms where a proton can occupy two ormore positions of a heterocyclic system including, but not limited to,1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds also include hydrates and solvates, as well as anhydrous andnon-solvated forms.

Compounds can also include all isotopes of atoms occurring in theintermediates or final compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. For example, isotopesof hydrogen include tritium and deuterium.

In some embodiments, the compounds, or salts thereof, are substantiallyisolated. Partial separation can include, for example, a compositionenriched in the compound. Substantial separation can includecompositions containing at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%, or at least about 99% by weight of the compound, orsalt thereof. Methods for isolating compounds and their salts areroutine in the art.

Although the disclosed compounds are suitable, other functional groupscan be incorporated into the compound with an expectation of similarresults. In particular, thioamides and thioesters are anticipated tohave very similar properties. The distance between aromatic rings canimpact the geometrical pattern of the compound and this distance can bealtered by incorporating aliphatic chains of varying length, which canbe optionally substituted or can comprise an amino acid, a dicarboxylicacid or a diamine. The distance between and the relative orientation ofmonomers within the compounds can also be altered by replacing the amidebond with a surrogate having additional atoms. Thus, replacing acarbonyl group with a dicarbonyl alters the distance between themonomers and the propensity of dicarbonyl unit to adopt ananti-arrangement of the two carbonyl moiety and alter the periodicity ofthe compound. Pyromellitic anhydride represents still anotheralternative to simple amide linkages which can alter the conformationand physical properties of the compound. Modern methods of solid phaseorganic chemistry (E. Atherton and R. C. Sheppard, Solid Phase PeptideSynthesis A Practical Approach IRL Press Oxford 1989) now allow thesynthesis of homodisperse compounds with molecular weights approaching5,000 Daltons. Other substitution patterns are equally effective.

Embodiments of various processes of preparing compounds of Formula (I)and salts thereof are provided. Where a variable is not specificallyrecited, the variable can be any option described herein, except asotherwise noted or dictated by context.

In some embodiments, the processes of preparing compounds of formula (I)or a pharmaceutically acceptable salt thereof is as described in theappended exemplary, non-limiting claims.

In some embodiments, processes or methods of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof are provided.In some embodiments, the methods comprise: contacting a compound ofFormula (II)

With a compound of Formula (III)

under suitable conditions to form a compound having the structure of

wherein:

A, B, and E are each independently N or CR₆;

X and Y are each independently O, S, or NR₇;

R₁ is H, OH, NH₂, NO₂, optionally substituted carbocycle, optionallysubstituted aryl group, optionally substituted heteroaryl group,branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, oralkylsulfanyl; and

R₂, R₃, R₄, R₅, R₆, and R₇, are each independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl,or optionally substituted cycloheteroalkyl; R₂ and R₃ are togetheroptionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl; or R₄ and R₅ are together optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecontacting is reacting. In some embodiments, the contacting iscondensing. In some embodiments, the contacting is coupling. In someembodiments, the contacting is cyclizing.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein A isN or CR₆. In some embodiments, A is N. In some embodiments, A is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein B isN or CR₆. In some embodiments, B is N. In some embodiments, B is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein E isN or CR₆. In some embodiments, E is N. In some embodiments, E is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isO, S, or NR₇. In some embodiments, X is O. In some embodiments, X is S.In some embodiments, X is NR₇.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein Y isO, S, or NR₇. In some embodiments, Y is O. In some embodiments, Y is S.In some embodiments, Y is NR₇.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is H, OH, NH₂, NO₂, optionally substituted carbocycle, optionallysubstituted aryl group, optionally substituted heteroaryl group,branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, oralkylsulfanyl. In some embodiments, R₁ is H. In some embodiments, R₁ isOH. In some embodiments, R₁ is NH₂. In some embodiments, R₁ is NO₂. Insome embodiments, R₁ is optionally substituted carbocycle. In someembodiments, R₁ is optionally substituted aryl group. In someembodiments, R₁ is optionally substituted heteroaryl group. In someembodiments, R₁ is branched or unbranched alkyl alcohol. In someembodiments, R₁ is halo. In some embodiments, R₁ is branched orunbranched alkyl. In some embodiments, R₁ is amide. In some embodiments,R₁ is cyano. In some embodiments, R₁ is alkoxy. In some embodiments, R₁is haloalkyl. In some embodiments, R₁ is aklylsulfonyl. In someembodiments, R₁ is nitrite. In some embodiments, R₁ is alkylsulfanyl.

In some embodiments, R₂ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl. In some embodiments, R₂ is H. In some embodiments, R₂is optionally substituted C₁-C₆ alkyl. In some embodiments, R₂ isoptionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₂ isoptionally substituted C₁-C₆ alkoxy. In some embodiments, R₂ isoptionally substituted cycloalkyl. In some embodiments, R₂ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₃is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₃ is H. In some embodiments, R₃ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₃ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₃ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₃ is optionallysubstituted cycloalkyl. In some embodiments, R₃ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₄is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₄ is H. In some embodiments, R₄ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₄ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₄ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₄ is optionallysubstituted cycloalkyl. In some embodiments, R₄ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₅is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₅ is H. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₅ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₅ is optionallysubstituted cycloalkyl. In some embodiments, R₅ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₆is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₆ is H. In some embodiments, R₆ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₆ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₆ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₆ is optionallysubstituted cycloalkyl. In some embodiments, R₆ is optionallysubstituted cycloheteroalkyl.

In some embodiments, R₇ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl. In some embodiments, R₇ is H. In some embodiments, R₇is optionally substituted C₁-C₆ alkyl. In some embodiments, R₇ isoptionally substituted C₁-C₆ hydroxyalkyl. In some embodiments, R₇ isoptionally substituted C₁-C₆ alkoxy. In some embodiments, R₇ isoptionally substituted cycloalkyl. In some embodiments, R₇ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are together optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl. In some embodiments, R₂ and R₃ aretogether optionally substituted cycloalkyl. In some embodiments, R₂ andR₃ are together optionally substituted cycloheteroalkyl.

In some embodiments, R₄ and R₅ are together optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl. In someembodiments, R₄ and R₅ are together optionally substituted cycloalkyl.In some embodiments, R₄ and R₅ are together optionally substitutedcycloheteroalkyl.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof further comprise coupling thecompound of

with the compound of

to form compounds of

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecoupling comprises reacting the compounds of Formula (II) and Formula(III) for at least about 5 minutes. In some embodiments, the reactingcomprises heating the reaction to a temperature of at least about 40° C.for at least about 1, 2, 3, 4, or 5 minutes.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof further comprise quenchingthe reaction of a compound of Formula (II) and a compound of Formula(III) to form a slurry comprising the compound of

or a pharmaceutically acceptable salt thereof. In some embodiments, thequenching comprises cooling and/or adding water to the reaction of acompound of Formula (II) and a compound of Formula (III) to quench thereaction to form the slurry.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof further comprise isolatingthe compound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises filtering, washing, and/or drying the slurry toobtain the compound of

or a pharmaceutically acceptable salt thereof.

In some embodiments, the isolating comprises filtering the slurry toobtain the compound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises washing the slurry to obtain the compound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises drying the slurry to obtain the compound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises filtering and drying the slurry to obtain thecompound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises filtering and washing the slurry to obtain thecompound of

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises washing and drying the slurry to obtain the compoundof

or a pharmaceutically acceptable salt thereof. In some embodiments, theisolating comprises filtering, washing, and drying the slurry to obtainthe compound of

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof comprisewashing to obtain the compound of

or a pharmaceutically acceptable salt thereof, wherein the washingcomprises washing with water and/or an organic solvent. In someembodiments, the washing comprise washing with solvents to removeimpurities such as unreacted or excess the compound of Formula (II) orthe compound of Formula (III), the byproducts derived from the couplingregent and/or additives, and any combination thereof. In someembodiments, the washing comprise washing with water. In someembodiments, the washing comprise washing with an organic solvent. Insome embodiments, the washing comprise washing with water and an organicsolvent. In some embodiments, the washing does not comprise washing withwater. In some embodiments, the washing does not comprise washing withan organic solvent.

In some embodies, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof comprisingthe steps of:

-   -   (a) adding a coupling reagent and optionally an additive to a        solution of a compound of

-   -    in a first organic solvent to form a mixture and stirring the        mixture for at least about 5 minutes;    -   (b) stirring the mixture of step (a) with a compound of

-   -   (c) heating the mixture of step (b) to a temperature of at least        about 40° C. and stirring the mixture under the temperature;    -   (d) cooling the mixture of step (c) and adding water to the        mixture to form a slurry;    -   (e) stirring the slurry of step (d);    -   (f) filtering the slurry of step (e) to obtain a solid;    -   (g) washing the solid of the step (f) with water and/or a second        organic solvent; and

(h) drying the solid of the step (g) at a temperature of at least about30° C. under vacuum to form the compound of

wherein the variables are defined herein.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecoupling reagent is a carbodiimide. In some embodiments, thecarbodiimides is DCC, DIC, or EDC hydrochloride. In some embodiments,the carbodiimides is DCC. In some embodiments, the carbodiimides is DIC.In some embodiments, the coupling reagent is EDC hydrochloride.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theadditive is HOBt, HOAt, or ethyl cyanohydroxyiminoacetate. In someembodiments, the additive is HOBt. In some embodiments, the additive isHOAt. In some embodiments, the additive is ethylcyanohydroxyiminoacetate.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thefirst organic solvent is a polar organic solvent. In some embodiments,wherein the polar organic solvent is a polar non-protonic organicsolvent. In some embodiments, the polar non-protonic organic solvent isdimethylformamide or diethylformamide. In some embodiments, the polarnon-protonic organic solvent is diethylformamide. In some embodiments,the polar non-protonic organic solvent is dimethylformamide.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theamount of the coupling reagent is at least about 1.0 equivalent in molarratio to the amount of the compound of Formula (II). In someembodiments, the amount of the coupling reagent is about 1.2 equivalentin molar ratio to the amount of the compound of Formula (II). In someembodiments, the amount of the additive is at least about 1.0 equivalentin molar ratio to the amount of the compound of Formula (II). In someembodiments, the amount of the additive is about 1.0 equivalent in molarratio to the amount of the compound of Formula (II).

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theconcentration of the compound of Formula (II) in the first organicsolvent is at least about 0.1 mol/L. In some embodiments, theconcentration of the compound of Formula (II) in the first organicsolvent is about 0.8 mol/L.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein inthe step (a), the mixture is stirred for at least about 5 minutes. Insome embodiments, in the step (a), the mixture is stirred for about 1hour.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theamount of the compound of Formula (III) is at least about 1.0 equivalentin molar ratio to the amount of the compound of Formula (II). In someembodiments, the amount of the compound of Formula (III) is about 1.2equivalent in molar ratio to the amount of the compound of Formula (II).

In some embodiments, in the step (b), the mixture is stirred for atleast 5 minutes. In some embodiments, in the step (b), the mixture isstirred for at least about 1 hour.

In some embodiments, in the step (c), the temperature is at least about60° C. In some embodiments, in the step (c), the temperature is at leastabout 75° C. In some embodiments, in the step (c), the temperature isabout 95° C. In some embodiments, in the step (c), the mixture of step(a) is heated to between about 90° C. and about 95° C. In someembodiments, in the step (c), the mixture of step (a) is heated tobetween about 85° C. and about 95° C. In some embodiments, in the step(c), the mixture of step (a) is heated to between about 80° C. and about95° C. In some embodiments, in the step (c), the mixture of step (a) isheated to between about 75° C. and about 95° C. In some embodiments, inthe step (c), the mixture of step (a) is heated to between about 95° C.and about 100° C. In some embodiments, in the step (c), the mixture ofstep (a) is heated to between about 95° C. and about 105° C. In someembodiments, in the step (c), the mixture of step (a) is heated tobetween about 95° C. and about 110° C. In some embodiments, in the step(c), the mixture of step (a) is heated to between about 90° C. and about115° C.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof, wherein in the step (c), themixture is stirred at the temperature for at least about 1, 2, 3, 4, or5 minutes. In some embodiments, in the step (c), the mixture is stirredat the temperature for at least about 1 hour. In some embodiments, inthe step (c), the mixture is stirred at the temperature for about 5hours. In some embodiments, in the step (c), the mixture is stirred atthe temperature for about 18 hours.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein inthe step (d), the mixture is cooled to about 5-25° C. I. In someembodiments, in the step (d), the mixture is cooled to about 15-20° C.

In some embodiments, in the step (d), the volume ratio of water to thefirst organic solvent is at least about 1. In some embodiments, in thestep (d), the volume ratio of water to the first organic solvent isabout 2.

In some embodiments, in the step (e), the mixture is stirred at about5-25° C. I. In some embodiments, in the step (e), the mixture is stirredat about 15-20° C.

In some embodiments, in the step (e), the slurry is stirred for at leastabout 5 minutes. In some embodiments, in the step (e), the slurry isstirred for about 1 hour.

In some embodiments, provided are processes of preparing compounds ofFormula (I), wherein in the step (g), the volume ratio of water to thefirst organic solvent in each wash cycle is at least about 0.5. In someembodiments, in the step (g), the volume ratio of water to the firstorganic solvent in each wash cycle is about 0.5.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thesolid is washed with water at least once. In some embodiments, the solidis washed with water twice.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thevolume ratio of the second organic solvent to the first organic solventin each wash cycle is at least about 0.5. In some embodiments, thevolume ratio of the second organic solvent to the first organic solventin each wash cycle is about 0.5.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thesolid is washed with the second organic solvent at least once. In someembodiments, the solid is washed with the second organic solvent twice.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thesecond organic solvent is an ether. In some embodiments, the ether is adialkyl ether. In some embodiments, the ether is methyl-tert-butylether.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thesolid is dried at about 55° C. In some embodiments, the solid is driedbetween about 45° C. to about 55° C. In some embodiments, the solid isdried between about 55° C. to about 65° C. In some embodiments, thesolid is dried between about 50° C. to about 60° C.

In some embodiments, also provided are processes of preparing compoundsof Formula (I), or a pharmaceutically acceptable salt thereof comprisingthe steps of:

-   -   (a) adding EDC hydrochloride and ethyl cyanohydroxyiminoacetate        to a solution of a compound of

-   -    in dimethylformamide to form a mixture and stirring the mixture        for at least about 1 hour;    -   (b) stirring the mixture of the step (a) with a compound of

-   -   (c) heating the mixture of the step (b) to a temperature at        about 95° C. and stirring the mixture under the temperature for        at least about 5 hour;    -   (d) cooling the mixture of the step (c) to about 15-20° C. and        adding water to form a slurry;    -   (e) stirring the slurry of the step (d) at about 15-20° C. for        about 1 h;    -   (f) filtering the slurry of the step (e) to from a solid;    -   (g) washing the solid of the step (f) with water and        methyl-tert-butyl ether; and

(h) drying the solid of the step (g) at about 55° C. under vacuum toform the compound of

wherein the variables are as defined herein.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein, inthe step (c), the mixture of step (b) is heated to or close to reflux.In some embodiments, in the step (c), the mixture of step (b) is heatedto about 95° C. In some embodiments, in the step (c), in the step (c),the mixture of step (b) is heated to between about 90° C. and about 95°C. In some embodiments, in the step (c), the mixture of step (b) isheated to between about 85° C. and about 95° C. In some embodiments, inthe step (c), the mixture of step (b) is heated to between about 80° C.and about 95° C. In some embodiments, in the step (c), the mixture ofstep (b) is heated to between about 75° C. and about 95° C. In someembodiments, in the step (c), the mixture of step (b) is heated tobetween about 95° C. and about 100° C. In some embodiments, in the step(c), the mixture of step (b) is heated to between about 95° C. and about105° C. In some embodiments, the mixture of step (b) is heated tobetween about 95° C. and about 110° C. In some embodiments, the mixtureof step (b) is heated to between about 90° C. and about 115° C.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof, further compriserecrystallizing the solid of the step (h) from a solvent. In someembodiments, the solvent for recrystallization is water,dimethylformadimade, ethanol, or methyl-tert-butyl ether. In someembodiments, the solvent for recrystallization is ethanol. In someembodiments, when the solvent for recrystallization is ethanol ormethyl-tert-butyl ether, the mixture forms a slurry.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein whenthe solvent for recrystallization is ethanol, the slurry is heated to atemperature of at least about 50° C. In some embodiments, when thesolvent is ethanol, the slurry is heated to a temperature of about 75°C. In some embodiments, the slurry is stirred at about 75° C. for about15 hours.

In some embodiments, when the solvent is methyl-tert-butyl ether, theslurry is heated to a temperature of at least about 30° C. In someembodiments, when the solvent is methyl-tert-butyl ether, the slurry isheated to a temperature of about 45° C. In some embodiments, the slurryis stirred at about 45° C. for about 15 hours.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thepurity of the recrystallized solid is at least about 95%. In someembodiments, the purity of the recrystallized solid is at least about99%. In some embodiments, the purity of the recrystallized solid is atabout 99.5%.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecolor of the recrystallized solid is white to off-white.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thesolid is dried at about 55° C. In some embodiments, the solid is driedbetween about 45° C. to about 55° C. In some embodiments, the solid isdried between about 55° C. to about 65° C. In some embodiments, thesolid is dried between about 50° C. to about 60° C.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof, wherein X is O.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof, wherein Y is O.

In some embodiments, processes of preparing compounds of Formula (I), ora pharmaceutically acceptable salt thereof, wherein the compound that isprepared or produced has a formula of

wherein the variables are as defined in claim 1. In some embodiments,processes of preparing compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound has a formula of

wherein the variables are as defined in claim 1. In some embodiments,processes of preparing compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound that is produced has aformula of

wherein the variables are as defined in claim 1. In some embodiments,processes of preparing compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound that is produced has aformula of

wherein the variables are as defined in claim 1. In some embodiments,processes of preparing compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound that is produced has aformula of

wherein the variables are as defined in claim 1

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₄and R₅ are each is independently H or optionally substituted C₁-C₆alkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, whereineither R₄ or R₅ is H.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,has a formula of

wherein the variables areas defined in claim 1.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,has a formula of

wherein the variables areas defined in claim 1.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are each is independently H or optionally substituted C₁-C₆alkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are both optionally substituted C₁-C₆alkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein bothR₂ and R₃ are methyl or ethyl. In some embodiments, provided areprocesses of preparing compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein both R₂ and R₃ are methyl. In someembodiments, provided are processes of preparing compounds of Formula(I), or a pharmaceutically acceptable salt thereof, wherein both R₂ andR₃ are ethyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,has a formula of

and R₁ is as defined in claim 1.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, whereineither R₂ or R₃ is H.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are together optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are together optionally substituted 5-, 6-, or 7-memberedcycloalkyl or cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is optionally substituted C₁-C₆ alkyl, optionally substitutedcarbocycle, optionally substituted aryl group, or optionally substitutedheteroaryl group.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is optionally substituted aryl group or optionally substitutedheteroaryl group.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is optionally substituted heteroaryl group.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is optionally substituted nitrogen-containing heteroaryl group.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₁is

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula (I) is

In some embodiments, also provided are processes of preparing thecompound having the structure of

or a pharmaceutically acceptable salt thereof comprising the steps of:

-   -   (a) adding EDC hydrochloride and ethyl cyanohydroxyiminoacetate        to a solution of

-   -    in dimethylformamide to form a mixture and stirring the mixture        for at least about 1 hour;    -   (b) stirring the mixture of the step (a) with

-   -    for about 1 hour;    -   (c) heating the mixture of the step (b) to a temperature at        about 95° C. and stirring the mixture under the temperature for        at least about 5 hour;    -   (d) cooling the mixture of the step (c) to about 15-20° C. and        adding water to the mixture form a slurry;    -   (e) stirring the slurry of the step (d) at about 15-20° C. for        about 1 h;    -   (f) filtering the slurry of the step (e) to from a solid;    -   (g) washing the solid of the step (f) with water and        methyl-tert-butyl ether; and    -   (h) drying the solid of the step (g) at least about 55° C. under        vacuum to form

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof furthercomprising a method of preparing a compound of

by contacting

with R₂R₃C═O under suitable conditions, wherein the variables are asdefined herein. In some embodiments, wherein the contacting is reacting.In some embodiments, the contacting is condensing. In some embodiments,the contacting is coupling. In some embodiments, the contacting iscyclizing.

In some embodiments, also provided are methods of preparing compounds of

comprising the steps of:

(a) adding pyrrolidine to a solution of a compound of

in a compound of R₂R₃C═O to form a mixture;

-   -   (b) heating the mixture of step (a) to reflux and stirring the        refluxing mixture for about 19.5 hours under the temperature,        cooling the mixture to about 15-20° C., and adding water to the        mixture;    -   (c) adjusting the pH of the mixture of step (b) to about 2 with        HCl;    -   (d) stirring the mixture of step (c) with n-heptane to form a        slurry and stirring the slurry at about 15-20° C. for about 1        hour, and filtering the slurry to form a solid; and    -   (e) washing the solid of step (d) with water and n-heptane; and    -   (g) drying the solid of step (e) at about 50° C. under vacuum to        form the compound of

-   -    wherein:

A, B, and E are each independently N or CR₆;

X and Y are each independently O, S, or NR₇,

R₄, R₅, R₆, and R₇, are each independently H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionallysubstituted C₁-C₆ alkoxy, optionally substituted cycloalkyl, oroptionally substituted cycloheteroalkyl or R₄ and R₅ are togetheroptionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein, inthe step (b), the mixture of step (a) is heated to reflux at or close tothe boiling point of the compound of R₂R₃C═O. In some embodiments, inthe step (b), the mixture of step (a) is heated to about 95° C. In someembodiments, in the step (b), the mixture of step (a) is heated tobetween about 90° C. and about 95° C. In some embodiments, in the step(b), the mixture of step (a) is heated to between about 85° C. and about95° C. In some embodiments, in the step (b), the mixture of step (a) isheated to between about 80° C. and about 95° C. In some embodiments, inthe step (b), the mixture of step (a) is heated to between about 75° C.and about 95° C. In some embodiments, in the step (b), the mixture ofstep (a) is heated to between about 95° C. and about 100° C. In someembodiments, in the step (b), the mixture of step (a) is heated tobetween about 95° C. and about 105° C. In some embodiments, in the step(b), the mixture of step (a) is heated to between about 95° C. and about110° C. In some embodiments, in the step (b), the mixture of step (a) isheated to between about 90° C. and about 115° C.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Ais N or CR₆. In some embodiments, A is N. In some embodiments, A is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Bis N or CR₆. In some embodiments, B is N. In some embodiments, B is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Eis N or CR₆. In some embodiments, E is N. In some embodiments, E is CR₆.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis O, S, or NR₇. In some embodiments, X is O. In some embodiments, X isS. In some embodiments, X is NR₇.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Yis O, S, or NR₇. In some embodiments, Y is O. In some embodiments, Y isS. In some embodiments, Y is NR₇.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R₂is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₂ is H. In some embodiments, R₂ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₂ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₂ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₂ is optionallysubstituted cycloalkyl. In some embodiments, R₂ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R₃is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₃ is H. In some embodiments, R₃ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₃ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₃ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₃ is optionallysubstituted cycloalkyl. In some embodiments, R₃ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₄is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₄ is H. In some embodiments, R₄ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₄ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₄ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₄ is optionallysubstituted cycloalkyl. In some embodiments, R₄ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₅is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₅ is H. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₅ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₅ is optionallysubstituted cycloalkyl. In some embodiments, R₅ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R₆is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₆ is H. In some embodiments, R₆ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₆ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₆ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₆ is optionallysubstituted cycloalkyl. In some embodiments, R₆ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R₇is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆hydroxyalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted cycloalkyl, or optionally substituted cycloheteroalkyl. Insome embodiments, R₇ is H. In some embodiments, R₇ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R₇ is optionallysubstituted C₁-C₆ hydroxyalkyl. In some embodiments, R₇ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₇ is optionallysubstituted cycloalkyl. In some embodiments, R₇ is optionallysubstituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R₂and R₃ are together optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl. In some embodiments, R₂ and R₃ aretogether optionally substituted cycloalkyl. In some embodiments, R₂ andR₃ are together optionally substituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R₄and R₅ are together optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl. In some embodiments, R₄ and R₅ aretogether optionally substituted cycloalkyl. In some embodiments, R₄ andR₅ are together optionally substituted cycloheteroalkyl.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof furthercomprising methods of preparing a compound of

by contacting a compound of a formula of R₁CN with ammonium hydroxideand wherein R₁ is H, OH, NH₂, NO₂, optionally substituted carbocycle,optionally substituted aryl group, optionally substituted heteroarylgroup, branched or unbranched alkyl alcohol, halo, branched orunbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl,nitrite, or alkylsulfanyl. In some embodiments, wherein the contactingis reacting. In some embodiments, the contacting is condensing. In someembodiments, the contacting is coupling. In some embodiments, thecontacting is cyclizing.

In some embodiments, also provided are methods of preparing a compoundof

comprising the steps of:

-   -   (a) adding hydroxylamine to a solution of a compound of R₁CN in        an alcohol form a mixture;    -   (b) heating the mixture of the step (a) to a temperature of        about 75° C. and stirring the mixture for about 4 hours under        the temperature to form a slurry    -   (c) cooling the slurry of the step (b) to ambient temperature        and stirring for about 16 hours under the ambient temperature;    -   (d) filtering the slurry of the step (c) to form a solid; and    -   (e) washing the solid of the step (d) with the alcohol and        drying the washed solid at about 50° C. under vacuum to form the        compound of

-   -    wherein R₁ is as defined herein.

In some embodiments, provided are processes of preparing compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein R₁is H, OH, NH₂, NO₂, optionally substituted carbocycle, optionallysubstituted aryl group, optionally substituted heteroaryl group,branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, oralkylsulfanyl. In some embodiments, R₁ is H. In some embodiments, R₁ isOH. In some embodiments, R₁ is NH₂. In some embodiments, R₁ is NO₂. Insome embodiments, R₁ is optionally substituted carbocycle. In someembodiments, R₁ is optionally substituted aryl group. In someembodiments, R₁ is optionally substituted heteroaryl group. In someembodiments, R₁ is branched or unbranched alkyl alcohol. In someembodiments, R₁ is halo. In some embodiments, R₁ is branched orunbranched alkyl. In some embodiments, R₁ is amide. In some embodiments,R₁ is cyano. In some embodiments, R₁ is alkoxy. In some embodiments, R₁is haloalkyl. In some embodiments, R₁ is aklylsulfonyl. In someembodiments, R₁ is nitrite. In some embodiments, R₁ is alkylsulfanyl.

In some embodiments, provided are processes of preparing compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, whereinthe alcohol is an optionally substituted C1-C6 alkyl alcohol. In someembodiments, the alcohol is methanol, ethanol, propanol, or butanol. Insome embodiments, the alcohol is ethanol. In some embodiments, thealcohol is methanol. In some embodiments, the alcohol is propanol. Insome embodiments, the alcohol is butanol.

In some embodiments, provided are processes of preparing compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, whereinthe hydroxylamine is hydroxylamine hydrochloride salt. In someembodiments, provided are processes of preparing compounds of Formula(III), or a pharmaceutically acceptable salt thereof, wherein when thehydroxylamine is hydroxylamine hydrochloride salt, an organic based isadded. In some embodiments, the organic based is diisopropylethylamine.In some embodiments, the amount of the organic based is at least about1.5 equivalent in molar ratio of the amount of hydroxylaminehydrochloride salt.

In some embodiments, provided are processes of preparing compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, in thestep (a), the amount of hydroxylamine is at least about 1.5 equivalentin molar ratio to the amount of R₁CN.

In some embodiments, provided are processes of preparing compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein,in the step (b), the mixture of step (a) is heated to reflux at or closeto the boiling point of the alcohol. In some embodiments, the mixture ofstep (a) is heated to about 75° C. In some embodiments, in the step (b),the mixture of step (a) is heated to between about 70° C. and about 75°C. In some embodiments, in the step (b), the mixture of step (a) isheated to between about 65° C. and about 75° C. In some embodiments, inthe step (b), the mixture of step (a) is heated to between about 60° C.and about 75° C. In some embodiments, in the step (b), the mixture ofstep (a) is heated to between about 75° C. and about 75° C. In someembodiments, in the step (b), the mixture of step (a) is heated tobetween about 75° C. and about 80° C. In some embodiments, in the step(b), the mixture of step (a) is heated to between about 75° C. and about85° C. In some embodiments, in the step (b), the mixture of step (a) isheated to between about 75° C. and about 90° C. In some embodiments, inthe step (b), the mixture of step (a) is heated to between about 90° C.and about 95° C.

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein thecompound of

is contacted with a coupling reagent, with or without the addictive, toform an intermediate having the structure of

wherein R₈ is optionally substituted C1-C6 alkyl and R₂, R₃, R₄, R₅, R₆,and R₇, are as defined herein, is provided. In some embodiments, whereinthe compound of Formula (II) reacts with the coupling reagent, with orwithout the addictive, to form the intermediate Formula (XIII). In someembodiments, wherein the compound of Formula (II) couples with thecoupling reagent, with or without the addictive, to form theintermediate Formula (XIII).

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theintermediate of Formula (XIII) is a compound having the structure of

In some embodiments, the intermediate of Formula (XIII) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XIII) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XIII) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XIII) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XIII) is a compoundhaving the structure of

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theintermediate having the structure of

further contacts the compound of

to form an intermediate having a structure of

In some embodiments, the intermediate of Formula (XIII) further reactswith the compound of Formula (III) to form an intermediate of Formula(XVI). In some embodiments, the intermediate of Formula (XIII) furthercouples with the compound of Formula (III) to form an intermediate ofFormula (XVI).

In some embodiments, the intermediate of Formula (XVI) is a compoundhaving the structure of

In some embodiments, wherein the intermediate of Formula (XVI) is acompound having the structure of

In some embodiments, the intermediate of Formula (XVI) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XVI) is a compoundhaving the structure of

In some embodiments, the intermediate of Formula (XVI) is a compoundhaving the structure of

In some embodiments, provided are processes of preparing compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein theintermediate having the structure of

further forms the compound of

under thermal cyclodehydration conditions. In some embodiments, theintermediate of Formula (XVI) further condenses to form the compound ofFormula (I) under thermal cyclodehydration conditions. In someembodiments, the intermediate of Formula (XVI) further cyclizes to formthe compound of Formula (I) under thermal cyclodehydration conditions.In some embodiments, wherein the compound of

In some embodiments, also provided are compounds of

or a pharmaceutically acceptable salt thereof, which are isolated fromthe processes as described herein.

In some embodiments, also provided compositions comprising one or morecompounds of

or a pharmaceutically acceptable salt thereof.

In some embodiments, also provided solutions comprising one or morecompounds of

or a pharmaceutically acceptable salt thereof.

In some embodiments, also provided are compounds of

or a pharmaceutically acceptable salt thereof, which are isolated fromthe processes as described herein.

In some embodiments, also provided compositions comprising one or morecompounds of

or a pharmaceutically acceptable salt thereof.

In some embodiments, also provided solutions comprising one or morecompounds of

or a pharmaceutically acceptable salt thereof.

In some embodiments, also provided are methods of forming a compound ofFormula I, the method comprising reacting the compound having thestructure of

under thermal cyclodehydration conditions to form a compound of

In some embodiments, provided are crystalline forms of the compoundhaving the structure

is provided. In some embodiments, the crystalline form is Form I. Insome embodiments, the crystalline Form I characterized by an X-raypowder diffraction pattern comprising peaks: at about 8.9±0.5 degrees2θ, at about 9.4±0.5 degrees 2θ, 15.7±0.5 degrees 2θ, at about 17.7±0.5degrees 2θ, at about 18.9±0.5 degrees 2θ, 24.3±0.5 degrees 2θ, at about26.0±0.5 degrees 2θ, and at about 26.7±0.5 degrees 2θ. In someembodiments, the crystalline Form I is characterized by an X-ray powderdiffraction pattern comprising one or more peaks as shown in FIG. 6. Insome embodiments, the crystalline Form I is characterized by an X-raypowder diffraction pattern comprising one or more peaks as shown inTable 14. In some embodiments, the crystalline Form I of claim 142characterized by an X-ray powder diffraction pattern comprising one ormore d-spacing values at about 10.0±0.5 degrees angstroms, at about9.4±0.5 degrees angstroms, at about 5.6±0.5 degrees angstroms, at about5.0±0.5 degrees angstroms, at about 4.7±0.5 degrees angstroms, at about3.7±0.5 degrees angstroms, at about 3.4±0.5 degrees angstroms, and atabout 3.3±0.5 degrees angstroms.

Although the compounds described herein may be shown with specificstereochemistries around certain atoms, such as cis or trans, thecompounds can also be made in the opposite orientation or in a racemicmixture. Such isomers or racemic mixtures are encompassed by the presentdisclosure. Additionally, although the compounds are shown collectivelyin a table, any compounds, or a pharmaceutically acceptable saltthereof, can be chosen from the table and used in the embodimentsprovided for herein.

In some embodiments, pharmaceutical compositions comprising a compoundor pharmaceutically salt thereof of any compound described herein areprovided.

The compounds described herein can be made by can be made according tothe methods described herein and in the examples. The methods describedherein can be adapted based upon the compounds desired and describedherein. In some embodiments, this method can be used to make one or morecompounds as described herein and will be apparent to one of skill inthe art which compounds can be made according to the methods describedherein.

The conditions and temperatures can be varied, such as shown in theexamples described herein. These schemes are non-limiting syntheticschemes and the synthetic routes can be modified as would be apparent toone of skill in the art reading the present specification. The compoundscan also be prepared according to the schemes described in the Examples.

The compounds can be used to modulate the S₁P₁ receptor. Thus, in someembodiments, the compounds can be referred to as S₁P₁ receptormodulating compounds

Although the compounds in the tables above or in the examples sectionare shown with specific stereochemistries around certain atoms, such ascis or trans, the compounds can also be made in the opposite orientationor in a racemic mixture.

In some embodiments, the present embodiments provide pharmaceuticalcompositions comprising a compound or pharmaceutically salt thereof anycompound described herein.

In some embodiments, the compounds are made according to schemesdescribed in the examples. The schemes can be used to prepare thecompounds and compositions described herein. The conditions andtemperatures can be varied, or the synthesis can be performed accordingto the examples described herein with modifications that are readilyapparent based upon the compound being synthesized.

The conditions and temperatures can be varied, such as shown in theexamples described herein. These schemes are non-limiting syntheticschemes and the synthetic routes can be modified as would be apparent toone of skill in the art reading the present specification.

The present disclosure also provides the following non-limitingembodiments:

In order that the embodiments disclosed herein may be more efficientlyunderstood, examples are provided below. It should be understood thatthese examples are for illustrative purposes only and are not to beconstrued as limiting the embodiments in any manner.

The following examples are illustrative, but not limiting, of theprocesses described herein. Other suitable modifications and adaptationsof the variety of conditions and parameters normally encountered intherapy, synthesis, and other embodiments disclosed herein are withinthe spirit and scope of the embodiments.

EXAMPLES Example 1: Processes of Preparing Compounds of Formula (I)

Certain synthetic schemes, both general and specific, are providedherein. The compounds disclosed herein can be made according to themethods described herein or intermediates that lead to the compoundsdisclosed herein can be made according to the methods described herein.The substitutions can be varied according to the compound orintermediate being made based upon the following examples and othermodifications known to one of skill in the art.

The processes disclosed herein were used to prepare the followingcompounds in the following examples or the examples were variedaccording to one of skill in the art to prepare the compounds.

General Procedure A:

Synthesis of Compound 2-2: N-Hydroxy-1H-pyrrazole-4-carboximidamide 2-2

Synthesis of Compound 2-2: N-Hydroxy-1H-pyrazole-4-carboximidamide

Based on the results seen in Table 1, EtOH was found to be the preferredsolvent for the synthesis of N-hydroxy-1H-pyrazole-4-carboximidamide(Compound 2-2).

TABLE 1 Reaction Condition Screen for Synthesis of Compound 2-2. Com-pound Sol- NH₂OH•HCl Base Temp 2-2 Yield Run vent Vol (eq.) (eq.) (° C.)(%)* (%) 1 EtOH 50 1.5 DIPEA 75 98.3 70.1 (2.0) 2 MeOH 50 1.0 TEA 6586.0 40.6 (1.0) 3 MeOH 25 1.5 TEA 65 100 22.1 (1.5) 4 MeOH 25 1.5 DIPEA65 98.7 29.5 (1.5) *Note: Compound 2-2 (%) = AUC (%) by HPLC

Next, the volume of ethanol (EtOH) was used for the isolation ofN-hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2) (Table 2). First,the volume of EtOH was decreased to 25 volumes (25 vol) of the Compound2-1 in Scheme 2. It was observed that by performing the reaction in alower volume of solvent, the product precipitated out of the reactionmixture upon completion of the reaction. A direct filtration wasutilized to isolate the desired product as a white solid (99.9% purity,84.9% yield). Next, different volumes of EtOH were studied. The yieldfor EtOH in 5, 10 and 20 volumes of the Compound 2-1 in Scheme 2 weresimilar. However a decrease in yield was observed with EtOH in 15volumes. The purity of the product was consistent which suggests thatthe quality of product was not dependent on the solvent loading. Thereaction was performed on a 25 g scale of Compound 2-1 using EtOH in 5,10 and 25 volumes of Compound 2-1 to study the impact of the yield on alarger scale (Table 3). It was observed the yield increased as thevolume of EtOH decreased. The volume of EtOH that provided the bestyield for the synthesis of N-hydroxy-1H-pyrazole-4-carboximidamide(Compound 2-2) was found to be 5 volumes (5 vol) of the Compound 2-1.This result could not have been predicted.

TABLE 2 Isolation Condition Screen for Synthesis of Compound 2-2. Com-Sol- NH2OH•HCl DIPEA Temp pound 2-2 Yield Run vent Vol (eq.) (eq.) (°C.) (%)* (%) 1 EtOH 50 1.5 2.0 75 98.3 70.1 2 EtOH 25 1.5 2.0 75 99.984.9 3 EtOH 20 1.5 2.0 75 99.9 77.5 4 EtOH 15 1.5 2.0 75 99.9 66.4 5EtOH 10 1.5 2.0 75 99.9 75.0 6 EtOH 5 1.5 2.0 75 99.9 76.5 *Note:Compound 2-2 (%) = AUC (%) by HPLC

TABLE 3 Volume of EtOH Screen for Synthesis of Compound 2-2 on 25 gScale. Com- EtOH NH2OH•HCl DIPEA Temp pound 2 Yield Run Scale (Vol)(eq.) (eq.) (° C.) (%)* (%) 1 25 g 25 1.5 2.0 75 99.9 59.8 2 25 g 10 1.52.0 75 99.9 63.7 3 25 g 5 1.5 2.0 75 98.7 67.3 *Note: Compound 2-2 (%) =AUC (%) by HPLC

Experimental of Synthesis of Compound 2-2:N-Hydroxy-H-pyrazole-4-carboximidamide

To a stirred solution of 4-cyanopyrazole (2-1, 25 g) in ethanol (125 mL)was added hydroxylamine hydrochloride (28 g) andN,N-diisopropylethylamine (DIPEA) (93.8 mL). The reaction was heated to75° C. and stirred for 4 hr. During the 4 hr stirring period, thereaction mixture became a white slurry. The slurry was cooled to ambienttemperature and stirred for 16 hr. The slurry was filtered to obtain asolid and the solid was washed with EtOH (50 mL×2). The collected solidwas dried at 50° C. under vacuum to yieldN-hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2) as a white solid(22.8 g, 67.3% yield). UPLC-qDa (C₄H₆N₄O) calcd 127.05 [M+H]⁺, found127.03.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 5.63 (s, 2H), 7.67 (bs, 1H), 7.96 (bs,1H), 9.11 (s, 1H), 12.87 (bs, 1H).

General Procedure B:

Synthesis of Compound 4-2:2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic Acid

Synthesis of Compound4-2:2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic Acid

The synthetic route in Scheme 4 involved reacting3-acetyl-4-hydroxy-benzoic acid Compound 4-1 with 3-pentanone in thepresence of pyrrolidine to yield2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid(Compound 2-2). The screening for reaction solvents began by carryingout the reaction in toluene (Table 4). The initial lab run followed theprocedure outlined in Patent WO 2000/03681 where pyrrolidine (0.5 eq.)and 3-pentanone (1.0 eq.) were added to hot toluene in an amount of 15volumes (15 vol) of Compound 4-1, followed by addition of3-acetyl-4-hydroxy-benzoic acid (Compound 4-1). The reaction mixture wasstirred at 80° C. for 24 hr and showed a low conversion of 3.0%. Next,the order of addition was changed where pyrrolidine and 3-pentanone wereadded to 3-acetyl-4-hydroxy-benzoic acid (Compound 4-1) in toluene. Theequivalences of pyrrolidine and 3-pentanone were increased as well inattempt to further progress the completion of reaction. The reaction wasslow in toluene and did not show high conversion to the desired product.Due to the slow kinetics of the reaction in a non-polar solvent such astoluene, polar solvents were screened. The reaction carried out in EtOHshowed 80.6% conversion after 48 hr. Next, acetic acid was incorporatedas an additive in attempt to increase the progression of the reaction byaiding the proton transfer occurring mechanistically. The addition ofacetic acid did not show a significant increase in conversion. Thereaction in isopropanol (IPA) showed similar results as EtOH. 1-Propanolwas included due to its higher boiling point, which would allow thereaction to be carried out at a higher temperature. The reaction in1-propanol showed a similar conversion as the reactions carried out inEtOH and IPA except in a shorter reaction time. 3-Pentanone wasincorporated as a solvent in which it would have a dual role in thereaction as both solvent and reagent. The reaction carried out in3-pentanone in an amount of the 10 volumes (10 vol) of Compound 4-1, at95° C. showed the highest conversion and the shortest reaction

TABLE 4 Reaction Condition Screen for Synthesis of Compound 4-2. TempReaction Time Pyrrolidine 3-Pentanone Compound 4-2 Run Solvent Vol (°C.) (hr) (eq.) (eq.) (%)* 1 Toluene 15 80 48 0.5 1.5 3.0 2 Toluene 15 8048 1.2 1.2 82.8 3 Toluene 15 90 48 1.5 1.5 72.7 4 EtOH 10 75 48 1.5 1.580.6 5** EtOH 10 75 48 1.5 1.5 83.4 6 EtOH 10 75 48 2.0 1.5 76.0 7 IPA10 75 24 2.0 1.5 68.8 8 1-Propanol 10 95 16 2.0 1.5 81.0 9 3-Pentanone10 95 15 2.0 — 95.5 *Note: Compound 4-2 (%) = AUC (%) by HPLC **0.5 eq.of Acetic Acid used as an additive

Encouraged by the results where 3-pentanone played a dual role as bothsolvent and reagent, the volume of 3-pentanone was examined (Table 5).The reaction was carried out in 2.5 volumes (2.5 vol) of Compound 4-1and the reaction showed a conversion of 71.9% at 16 hr. Additional3-pentanone (1.25 vol) was added to the reaction and the conversionincreased to 90.6% at 21 hr. The reaction was carried out in 3-pentanone(5 vol) and the reaction showed a conversion of 73.2% at 16 hr.Additional 3-pentanone (1.25 vol) was added to the reaction and theconversion increased to 92.6% at 21 hr. Based on the results seen in Run2, the reaction was carried out in 3-pentanone (6.25 vol) and 100%conversion was observed at 19 hr. It was found that the reactionproceeded at a faster rate and went to completion with the excess3-pentanone (6.25 vol) being initially used during the reaction. Thevolume of 3-pentanone as a solvent that provided the best yield wasfound to be 6.25 volumes of Compound 4-1.

TABLE 5 Volume of 3-Pentanone Screen for Synthesis of Compound 4-2.Reaction Com- Temp Time Pyrrolidine pound 4-2 Run Solvent Vol (° C.)(hr) (eq.) (%)* 1** 3-Pentanone 2.5 95 21 2.0 90.6 2** 3-Pentanone 5.095 21 2.0 92.6 3 3-Pentanone 6.25 95 19 2.0 100 *Note: Compound 4-2 (%)= AUC (%) by HPLC **Additional 3-pentanone (1.25 vol) added to progressthe reaction to reported conversion.

Crystallization conditions were developed for the isolation of2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid Compound4-2 (Table 6). The initial isolation of the product involved anacid-base extraction to yield Compound 4-2 as a yellow solid. Thereaction mixture was diluted with ethyl acetate (EtOAc) and the pH wasadjusted to 2 using 0.5 M HCl. Phase separation was carried out and thepH of the organic layer was adjusted to 5 using 5 M NaOH. The organiclayer was concentrated under pressure to yield the desired product as acrystalline yellow solid. Next, direct crystallization from the reactionmixture was studied. It was found that crystallization occurred by firstadding H₂O followed by adjusting the pH of the reaction mixture to 2using 5 M HCl to form a slurry. The slurry was filtered to yieldCompound 4 as a yellow solid with a 59.8% yield. Different solvents werescreened in attempts to improve the yield. Solids were not isolated whenacetone and IPA were used as anti-solvents. n-Heptane was added to theslurry at 20° C. after the pH adjustment which resulted in a minorincrease in yield. Next, the addition of n-heptane to the slurry at10-15° C. caused a yield increase of 77.4%. These conditions were foundto enhance the crystallization for2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid(Compound 4-2).

TABLE 6 Isolation Condition Screen for Synthesis of Compound 4-2.Compound Isolation Anti- Temp Yield 4-2 Run Technique Solvent solvent (°C.) (%) (%)* 1 Acid-Base EtOAc — 20 60.3 100 Extraction 2Crystallization H₂O 5M HCl 20 59.8 100 3 Crystallization H₂O Acetone 20— — 4 Crystallization H₂O IPA 20 — — 5 Crystallization H₂O n-Heptane 2061.4 100 6 Crystallization H₂O n-Heptane 10-15 77.4 100 *Note: Compound4-2 (%) = AUC (%) by HPLC

Experimental of Synthesis of Compound 4-2:2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic Acid

To a stirred solution of 3-acetyl-4-hydroxy-benzoic acid (Compound 4-1,20 g) in 3-pentanone (125 mL) was added pyrrolidine (18.5 mL). Thereaction was heated to 95° C. and stirred for 19.5 hr. The reaction wascooled to 15-20° C. and H₂O (60 mL) was added to form a slurry. The pHof the slurry was adjusted to 2 by addition of 5 M HCl, aq. (55 mL).n-Heptane (60 mL) was added and the slurry was stirred at 15-20° C. forapproximately 1 hr. The slurry was filtered and the solid was washedwith water (20 mL×2) and n-heptane (20 mL×2). The collected solid wasdried at 50° C. under vacuum to yield2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid Compound4-2 as a yellow solid (17.8 g, 64.5% yield).

UPLC-qDa (C₁₄H₁₆O₄) calcd 249.11 [M+H]⁺, found 249.19. ¹H NMR (500 MHz,CDCl₃) δ ppm 0.95-0.98 (t, J=7.44 Hz, 6H), 1.74-1.87 (m, 4H), 2.79 (s,2H), 7.03-7.05 (d, J=8.78 Hz, 1H), 8.19-8.21 (dd, J=8.78, 2.20 Hz, 1H),8.65 (d, J=2.2 Hz, 1H).

FIG. 4 shows the result of Polarized Light Microscopy (PLM) Analysis of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1) (10 m Scale) and one of skill in the art will understandthat the result is generated by the traditional Polarized LightMicroscopy method, which is known and appreciated by the one of skill inthe art:

FIG. 5 shows the result of Differential thermal analysis. (DSC) of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1) and one of skill in the art will understand that theresult is generated by the traditional Polarized Light Microscopymethod, which is known and appreciated by the one of skill in the art:

FIG. 6 and Table show the result of X-ray powder diffraction (XRPD)results of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1) and one of skill in the art will understand that theresult is generated by the traditional Polarized Light Microscopymethod, which is known and appreciated by the one of skill in the art:

TABLE 14 X-ray powder diffraction (XRPD) results of6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5- yl)-2,2-diethylchroman-4-one(Compound 6-1). XRPD peaks in FIG. 6 are indexed and listed herein. NetGross Rel. Index Angle d Value Intensity Intensity Intensity 1  8.003°11.03897 Å 210 919  1.1% 2  8.501° 10.39263 Å 450 1089  2.3% 3  8.853°9.98053 Å 19893 20478 100.0% 4  9.403° 9.39772 Å 19771 20266  99.4% 512.804° 6.90809 Å 94.5 313  0.5% 6 13.105° 6.75037 Å 465 677  2.3% 714.055° 6.29621 Å 45.2 239  0.2% 8 14.205° 6.22987 Å 175 368  0.9% 914.857° 5.95798 Å 849 1056  4.3% 10 15.055° 5.87996 Å 199 411  1.0% 1115.506° 5.71006 Å 2289 2509  11.5% 12 15.706° 5.63778 Å 17312 17533 87.0% 13 16.606° 5.33417 Å 885 1098  4.4% 14 17.043° 5.19850 Å 93.6 300 0.5% 15 17.156° 5.16429 Å 17.2 223  0.1% 16 17.707° 5.00498 Å 2102 2315 10.6% 17 17.857° 4.96327 Å 726 941  3.6% 18 18.058° 4.90850 Å 144 360 0.7% 19 18.857° 4.70211 Å 10882 11090  54.7% 20 22.059° 4.02630 Å 668835  3.4% 21 23.760° 3.74181 Å 796 1013  4.0% 22 24.010° 3.70341 Å 13481575  6.8% 23 24.260° 3.66587 Å 3818 4054  19.2% 24 24.806° 3.58637 Å1223 1471  6.1% 25 24.960° 3.56460 Å 971 1221  4.9% 26 25.410° 3.50243 Å1397 1648  7.0% 27 26.010° 3.42298 Å 4318 4563  21.7% 28 26.261° 3.39092Å 1051 1290  5.3% 29 26.711° 3.33479 Å 4077 4300  20.5% 30 27.310°3.26290 Å 91.9 286  0.5% 31 27.661° 3.22230 Å 99.1 272  0.5% 32 28.462°3.13347 Å 117 272  0.6% 33 28.662° 3.11206 Å 85.3 243  0.4% 34 28.812°3.09616 Å 52.7 212  0.3% 35 29.062° 3.07013 Å 440 601  2.2% 36 29.412°3.03436 Å 97.2 257  0.5% 37 29.762° 2.99942 Å 206 362  1.0% 38 30.011°2.97515 Å 214 364  1.1% 39 30.918° 2.88992 Å 19.5 168  0.1% 40 31.338°2.85210 Å 175 333  0.9% 41 32.013° 2.79349 Å 284 448  1.4% 42 32.313°2.76824 Å 51.2 213  0.3% 43 32.414° 2.75986 Å 96.0 257  0.5% 44 32.813°2.72717 Å 184 337  0.9% 45 32.912° 2.71919 Å 97.2 248  0.5% 46 33.212°2.69533 Å 148 289  0.7% 47 33.764° 2.65255 Å 119 250  0.6% 48 34.764°2.57847 Å 627 768  3.2% 49 35.314° 2.53959 Å 44.1 188  0.2% 50 35.864°2.50189 Å 659 800  3.3% 51 36.265° 2.47515 Å 73.9 209  0.4% 52 36.666°2.44900 Å 72.0 207  0.4% 53 37.516° 2.39541 Å 288 430  1.4%

General Procedure C:

Example 2: Synthesis of Compound6-1:6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

Synthesis of Compound6-1:6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

2-Methyltetrahydrofuran (MeTHF) was screened as a potential solvent forthe synthesis of Compound 6-1 (Table 7). An alternative solvent wasstudied because DMF can be difficult to purge due to its low evaporationrate. The reaction was carried out in MeTHF (10 vol) in 10 volumes ofCompound 4-2 at 75° C. Over the course of the reaction, the reactionmixture became very viscous and isolation of the product proved to bedifficult. The reaction produced Compound 4-2 in 21.9% yield. Forcomparison purpose, a reaction was carried out in DMF (10 vol) in 10volumes of Compound 4-2 at 95° C. in parallel. The isolation of theCompound 6-1 was obtained via crystallization with 64.3% yield. DMF wasfound to be the an appropriate solvent for the synthesis of Compound6-1.

TABLE 7 Solvent Screen for Synthesis of Compound 6-1. Temp Reaction TimeEDCI Oxyma Compound 2-2 Yield Run Solvent Vol (° C.) (hr) (eq.) (eq.)(eq.) (%) 1 MeTHF 10 75 16 1.2 1.0 1.2 21.9 2 DMF 10 95 18 1.2 1.0 1.264.3

Volumes of DMF were screened to identify the concentration for thereaction and crystallization (Table 8). The reaction carried out in DMF(15 vol) in 15 volumes of Compound 4-2 resulted in a low yield whichcould be caused to the solubility of the product in DMF. The reactioncarried out DMF (2.5 vol) in 2.5 volumes of Compound 4-2 became veryviscous and isolation of the product proved to be difficult. Even thoughthe reaction resulted in a good yield, the purity of Compound 6-1 wasfound to be low. The reactions carried out in DMF (5 vol and 10 vol) in5 and 10 volumes of Compound 4-2 showed promising results with similaryield. The volume of DMF for in one embodiments of the reaction wasfound to be 5 volumes of Compound 4-2.

TABLE 8 Volume of DMF Screen for Synthesis of Compound 6-1. TempReaction Time EDCI Oxyma Compound 2-2 Yield Compound 6-1 Run Solvent Vol(° C.) (hr) (eq.) (eq.) (eq.) (%) (%)* 1 DMF 15 95 14.5 1.2 1.0 1.2 34.696.2 2 DMF 10 95 18 1.2 1.0 1.2 71.5 97.3 3 DMF 5 95 18 1.2 1.0 1.2 72.797.9 4 DMF 2.5 95 20 1.2 1.0 1.2 75.9 58.9 *Note: Compound 6-1 (%) = AUC(%) by HPLC

The initial isolation technique for Compound 6-1 involved columnchromatography. The isolation of the desired Compound 6-1 via columnchromatography resulted in a low yield of 34.6%. Crystallizationconditions were screened to eliminate chromatography (Table 9). Directcrystallization from the reaction mixture was explored for the isolationof Compound 6-1. The addition of water to the reaction mixture initiatedcrystallization of the desired Compound 6-1. The appearance of Compound6-1 was reported as a white solid in Patent Application Publication WO2018/231745. However, the solid isolated from the crystallization was atan solid. In the attempt to improve the appearance of the solid and theyield, the addition of anti-solvent was explored. The addition of H₂Ofollowed by 5 M NaOH at 20° C. resulted in a slight improvement inappearance but a lower yield of 64.3%. Next, the addition of H₂O and 5 MNaOH at 5° C. showed a small increase in yield. The addition of H₂Ofollowed by 5 M HCl at 20° C. resulted in a minor improvement inappearance and a lower yield of 63.5%. Incorporating MeOH as ananti-solvent resulted in a significant decrease in yield. The additionof water to the reaction mixture at 5° C. resulted in a similar yieldwhen compared to the addition performed at 20° C. Higher volumes ofwater were explored, and it was found that the yield did not increasesignificantly with the increased volume of water. Based on yield andappearance, crystallization via the addition of H₂O (10 vol) in 10volumes of Compound 4-2 at 20° C. was found to be the best condition forthe isolation of Compound 6-1.

TABLE 9 Isolation Condition Screen for Synthesis of Compound 6-1.Isolation Solvent Anti- Temp Yield Run Technique (Vol) solvent (° C.)(%) 1 Column — — — 34.6 Chromatography 2 Crystallization H₂O (5) — 2071.5 3 Crystallization H₂O (5) 5M NaOH 20 64.3 4 Crystallization H₂O (5)5M NaOH 5 71.2 5 Crystallization H₂O (5) 5M HCl 20 63.5 6Crystallization H₂O (5) MeOH 20 30.8 7 Crystallization H₂O (5) — 5 69.98 Crystallization H₂O (10) — 20 72.8 9 Crystallization H₂O (15) — 2073.4

Crystallization of Compound 6-1 resulted in a crystalline tan solid. Thepresence of Oxyma in the product was a potential contributing factor tothe color of the product therefore the Oxyma loading was screened (Table10). The progression of the reaction decreased considerably with thelower Oxyma loading. The lower Oxyma loading did not improve theappearance of the Compound 6-land resulted in a substantial decrease inyield.

TABLE 10 Reagent Loading Screen for Synthesis of Compound 6-1. TempReaction Time EDCI Oxyma Compound 2-2 Yield Run Solvent Vol (° C.) (hr)(eq.) (eq.) (eq.) (%) 1 DMF 5 95 24 1.2 0.10 1.0 31.8 2 DMF 5 95 24 1.20.25 1.0 42.0 3 DMF 5 95 24 1.2 0.50 1.0 45.6

Different color remediation conditions were screened to improve theappearance of Compound 6-1. The purity and potency (% w/w) of the drugsubstance was analyzed concurrently. The potency was tabulated based onthe input material being normalized to 100%. First, recrystallization ofthe tan Compound 6-1 was explored as a color remediation method toimprove the appearance of Compound 6-1 (Table 11). DMF and dimethylsulfoxide (DMSO) were chosen due to the fact that Compound 6-1 wassoluble in these two solvents. The tan Compound 6-1 was brought intosolution with the noted solvent at the desired temperature and stirredfor 4 hr. Crystallization occurred upon the addition of water at 15-20°C. and the solid was obtained via filtration. Recrystallization in DMSOat 20° C. resulted in improved appearance, purity and potency. Differenttemperatures were screened for the recrystallization in DMF. The highertemperatures in DMF yielded a decrease in both the potency and recoveryof the final Compound 6-1.

TABLE 11 Color Remediation Screen for Recrystallization of tan Compound6-1 Compound Recov- Vol of Temp Purity 6-1 ery Solvent (° C.) Appearance(%)* (% w/w) (%) Input — — Orangish- 95.8 100 — White DMSO 5 20 OffWhite 98.3 106.9 84.4 to White DMF 5 20 Off White 97.7 107.1 83.0 toWhite DMF 5 45 Off White 97.8 101.7 82.2 to White DMF 5 90 Off White97.4 102.0 77.3 to White *Note: Purity (%) = AUC (%) by HPLC

Next, charcoal treatment was utilized as a color remediation approach(Table 12). DMF and DMSO were used as solvents due to the solubility ofCompound 6-1. The charcoal treatment comprised of activated charcoal (5wt %) being charged to a solution of the tan Compound 6-1 in the notedsolvent and stirred at 20° C. for 5 hr. The charcoal was filtered off,crystallization occurred upon the addition of water at 15-20° C. and thesolid was obtained via filtration. The charcoal treatment in DMFresulted in an increase in both purity and potency with a 63.4%recovery. The charcoal treatment in DMSO showed a slightly lower purityand potency but a higher recovery of 70.4% when compared to DMF.

TABLE 12 Color Remediation Screen: Charcoal Treatment Vol of PurityCompound 6-1 Recovery Solvent Appearance (%)* (% w/w) (%) Input —Orangish- 97.3 100 — White DMF & 5 Off White 99.3 107.3 63.4 Charcoal toWhite DMSO & 5 Off White 98.9 104.8 70.4 Charcoal to White *NOTE: Purity(%) = AUC (%) by HPLC

Another approach for color remediation was to reslurry the tan Compound6-1 in different solvents in which it exhibited low solubility. Varioussolvents were screened for the reslurry (Table 13). The reslurryprocedure involved stirring the Compound 6-1 in the desired solvent atthe noted temperature for 15 hr. The final Compound 6-1 was isolated viafiltration. The isolated solid from the reslurry in MeOH, EtOAc, andacetone showed a visual improvement in color. However, the reslurry inthese solvents resulted in such a low recovery that the purity andpotency were not analyzed. Reslurry in MTBE at 45° C. produced a whiteto off-white solid with 97.2% purity, 101.8% potency and 81.2% recovery.Different solvent volumes and temperatures were screened for thereslurry in EtOH. The isolated solid from the reslurry in EtOH (10 vol)in 10 volumes of Compound 6-1 at 45° C. showed a visual improvement incolor. However, the reslurry resulted in such a low recovery that thepurity and potency were not analyzed. The final Compound 6-1 obtainedfrom the reslurry in EtOH (10 vol) at 20° C. yielded a 98.7% purity,101.7% potency and 75.7% recovery. The final Compound 6-1 obtained fromthe reslurry in EtOH (5 vol) in 5 volumes of Compound 6-1 at 75° C.yielded a 99.8% purity, 105.6% potency and 66.0% recovery.

The recrystallization and charcoal treatment in DMSO and DMF were notchosen as the color remediation procedures. They did yield favorableimprovements to the Compound 6-1. However, both solvents would bedifficult to purge due to the high boiling point of each. The reslurryin EtOH (5 vol) in volumes of Compound 6-1 at 75° C. showed the mostpromising results and was chosen as the color remediation method for tanCompound 6-1.

TABLE 13 Color Remediation Screen: Reslurry Compound Recov- Vol of TempPurity 6-1 ery Solvent (° C.) Appearance (%)* (% w/w) (%) Input — —Orangish- 97.3 100   — White MeOH 10 20 Off White — — 11.0 to WhiteEtOAc 10 45 Off White — — 53.3 to White Acetone 10 20 Off White — — 33.0to White MTBE 10 45 Off White 97.2 101.8 81.2 to White EtOH 10 20 OffWhite 98.7 101.7 75.7 to White EtOH 10 45 Off White — — 45.3 to WhiteEtOH 5 75 Off White 99.8 105.6 66.0 to White *Note: Purity (%) = AUC (%)by HPLC

Experimental of Synthesis of Compound6-1:6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

To a stirred solution of2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid(Compound 4-2, 70 g) in N,N-dimethylformamide (DMF, 350 mL) was addedEDCI (64.9 g) and ethyl cyanohydroxyiminoacetate (Oxyma, 40.1 g). Thereaction was stirred at ambient temperature for 1 hr.N-Hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2, 42.7 g) was addedand the reaction was stirred at ambient temperature for 1 hr. Thereaction was heated to 95° C. and stirred for 5 hr. The reaction wascooled to 15-20° C. and H₂O (700 mL) was added to form a slurry. Theslurry was stirred at 15-20° C. for approximately 1 hr. The slurry wasfiltered to obtain a solid and the solid was washed with water (175mL×2) and methyl-t-butyl ether (“MTBE”) (175 mL×2). The collected solidwas dried at 55° C. under vacuum to yield the tan Compound 6-1 as a tansolid (75.2 g).

The tan Compound 6-1 was stirred with EtOH (375 mL) to form a slurry andthe slurry was heated to 75° C. The slurry was held at 75° C. for 16 hr.The slurry was cooled to 15-20° C. and stirred for approximately 1 hr.The slurry was filtered and the solid was washed with EtOH (100 mL×3).The collected solid was dried at 55° C. under vacuum to yield6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one(Compound 6-1) as a white to off-white solid (63.2 g, 66.2% yield).

UPLC-qDa (C₁₈H₁₈N₄O₃) calcd 339.15 [M+H]⁺, found 339.14.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88-0.91 (t, J=7.44 Hz, 6H), 1.70-1.81(m, 4H), 2.92 (s, 2H), 7.26-7.28 (d, J=8.78 Hz, 1H), 8.06 (s, 1H),8.25-8.28 (dd, J=8.66, 2.32 Hz, 1H), 8.43-8.44 (d, J=2.20 Hz, 1H), 8.48(s, 1H), 13.48 (bs, 1H).

Ester Intermediates of Synthesis of Compound 6-1:6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

The one-pot process in Scheme 7 consisted of two distinct chemicalbond-forming transformations. First, an esterification occurred byactivation of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylicacid (Compound 4-2) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDCI) and ethyl cyanohydroxyiminoacetate (Oxyma) to yield Intermediate7-1. Next, esterification occurred by activation of Intermediate 7-1 inthe presence of N-hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2)to yield Intermediate 7-2. The esterification between Compound 4-2 andCompound 2-2 was then followed by thermal cyclodehydration to yieldCompound 6-1. The two transient intermediates were isolated andcharacterized in the traditional methods that one of skill in the artwould know and use for in-process analysis purposes.

Intermediate 7-1: ethyl(Z)-2-cyano-2-(((2,2-diethyl-4-oxochromane-6-carbonyl)oxy)imino)acetate

¹H-NMR of Oxyma Ester Intermediate 7-1: ¹H NMR (500 MHz, CDCl₃) δ ppm0.95-0.98 (t, J=7.44 Hz, 6H), 1.44-1.47 (t, J=7.08 Hz, 3H), 1.74-1.88(m, 4H), 2.80 (s, 2H), 4.50-4.54 (q, J=7.16 Hz, 2H), 7.09-7.10 (d,J=8.78 Hz, 1H), 8.22-8.25 (dd, J=8.78, 2.22 Hz, 1H), 8.69-8.70 (d,J=2.20 Hz, 1H).

Intermediate 7-2:N-((2,2-diethyl-4-oxochromane-6-carbonyl)oxy)-1H-pyrazole-4-carboximidamide

¹H-NMR of Oxyma Ester Intermediate 7-2: ¹H NMR (400 MHz, CDCl₃) δ ppm0.85-0.88 (t, J=7.22 Hz, 6H), 1.61-1.78 (m, 4H), 2.67 (s, 2H), 5.93 (bs,2H), 6.86-6.88 (d, J=8.59 Hz, 1H), 7.85 (s, 2H), 8.05-8.08 (dd, J=8.78,1.95 Hz, 1H), 8.39-8.40 (d, J=1.95 Hz, 1H).

What is claimed is: 1-146. (canceled)
 147. A process of preparing acompound of Formula (I), or a pharmaceutically acceptable salt thereof,the process comprising: contacting a compound of

with a compound of

 under suitable conditions to produce the compound having the formula of

wherein: A, B, and E are each independently N or CR₆; X and Y are eachindependently O, S, or NR₇; R₁ is H, OH, NH₂, NO₂, optionallysubstituted carbocycle, optionally substituted aryl group, optionallysubstituted heteroaryl group, branched or unbranched alkyl alcohol,halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl,aklylsulfonyl, nitrite, or alkylsulfanyl; and R₂, R₃, R₄, R₅, R₆, andR₇, are each independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl; R₂ and R₃ are together optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl; or R₄ and R₅ aretogether optionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl.
 148. The process of claim 1, wherein the processcomprises the steps of: (a) adding a coupling reagent and optionally anadditive to a solution of a compound of

 in a first organic solvent to form a mixture and stirring the mixturefor at least about 5 minutes; (b) stirring the mixture of step (a) witha compound of

(c) heating the mixture of step (b) to a temperature of at least about40° C. and stirring the mixture under the temperature; (d) cooling themixture of step (c) and adding water to the mixture to form a slurry;(e) stirring the slurry of step (d); (f) filtering the slurry of step(e) to obtain a solid; (g) washing the solid of the step (f) with waterand/or a second organic solvent; and (h) drying the solid of the step(g) at a temperature of at least about 30° C. under vacuum to form thecompound of

 wherein the variables are as defined in claim
 1. 149. The process ofclaim 1, wherein the process comprises the steps of: (a) adding EDChydrochloride and ethyl cyanohydroxyiminoacetate to a solution of acompound of

 in dimethylformamide to form a mixture and stirring the mixture for atleast about 1 hour; (b) stirring the mixture of the step (a) with acompound of

(c) heating the mixture of the step (b) to a temperature at about 95° C.and stirring the mixture under the temperature for at least about 5hour; (d) cooling the mixture of the step (c) to about 15-20° C. andadding water to form a slurry; (e) stirring the slurry of the step (d)at about 15-20° C. for about 1 h; (f) filtering the slurry of the step(e) to form a solid; (g) washing the solid of the step (f) with waterand methyl-tert-butyl ether; and (h) drying the solid of the step (g) atabout 55° C. under vacuum to form the compound of

 wherein the variables are as defined in claim
 1. 150. The process ofclaim 3, further comprising recrystallizing the solid of the step (h)from a solvent.
 151. The process of claim 1, wherein the compound ofFormula (I) or a pharmaceutically acceptable salt thereof, has a formulaof

wherein the variables are as defined in claim.
 152. The process of claim5, wherein R₂ and R₃ are each independently H or optionally substitutedC₁-C₆ alkyl.
 153. The process of claim 1, wherein the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, has astructure of

and R₁ is as defined in claim
 1. 154. The process of claim 7, wherein R₁is optionally substituted C₁-C₆ alkyl, optionally substitutedcarbocycle, optionally substituted aryl group, or optionally substitutedheteroaryl group.
 155. The process of claim 7, wherein R₁ is


156. The process of claim 1, wherein the compound of Formula (I) is


157. The process of claim 10, wherein the process comprises the stepsof: (a) adding EDC hydrochloride and ethyl cyanohydroxyiminoacetate to asolution of

in dimethylformamide to form a mixture and stirring the mixture for atleast about 1 hour; (b) stirring the mixture of the step (a) with acompound of

 for about 1 hour; (c) heating the mixture of the step (b) to atemperature at about 95° C. and stirring the mixture under thetemperature for at least about 5 hour; (d) cooling the mixture of thestep (c) to about 15-20° C. and adding water to the mixture to form aslurry; (e) stirring the slurry of the step (d) at about 15-20° C. forabout 1 h; (f) filtering the slurry of the step (e) to form a solid; (g)washing the solid of the step (f) with water and methyl-tert-butylether; and (h) drying the solid of the step (g) at least about 55° C.under vacuum to form


158. The process of claim 1, further comprising a method of preparing acompound of

by contacting

with R₂R₃C═O under suitable conditions, and wherein the variables are asdefined in claim
 1. 159. The process of claim 12, wherein the methodcomprises the steps of: (a) adding pyrrolidine to a solution of acompound of

 in a compound of R₂R₃C═O to form a mixture; (b) heating the mixture ofstep (a) to reflux, stirring the mixture for about 19.5 hours under thetemperature, cooling the mixture to about 15-20° C., and adding water tothe mixture (c) adjusting the pH of the mixture of step (b) to about 2with HCl; (d) stirring the mixture of step (c) with n-heptane to form aslurry and stirring the slurry at about 15-20° C. for about 1 hour, andfiltering the slurry to form a solid; and (e) washing the solid of step(d) with water and n-heptane; and (g) drying the solid of step (e) atabout 50° C. under vacuum to form the compound of

 wherein the variables are as defined in claim
 1. 160. The process ofclaim 13, wherein the compound of

contacts the coupling reagent, with or without the addictive, to form anintermediate having the formula of

wherein R₂, R₃, R₄, and R₅, are each independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted cycloalkyl,or optionally substituted cycloheteroalkyl; or R₂ and R₃ are togetheroptionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl; or R₄ and R₅ are together optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl; R₈ is optionallysubstituted C₁-C₆ alkyl; and X, Y, A, B, and E are defined in claim 1.161. The process of claim 14, wherein the intermediate is a compoundhaving the structure of


162. The process of claim 12, wherein the intermediate having thestructure of

further contacts the compound of

to form an intermediate having a structure of

wherein the variables are as defined in claim
 1. 163. The process ofclaim 16, wherein the intermediate is a compound having the structure of


164. A crystalline form of a compound having the formula of

wherein the form is Form I of the compound.
 165. The crystalline Form Iof claim 18 characterized by an X-ray powder diffraction patterncomprising one or more peaks at about 8.9±0.5 degrees 2θ, at about9.4±0.5 degrees 2θ, 15.7±0.5 degrees 2θ, at about 17.7±0.5 degrees 2θ,at about 18.9±0.5 degrees 2θ, 24.3±0.5 degrees 2θ, at about 26.0±0.5degrees 2θ, and at about 26.7±0.5 degrees 2θ.
 166. The crystalline FormI of claim 19 characterized by an X-ray powder diffraction patterncomprising one or more d-spacing values at about 10.0±0.5 degreesangstroms, at about 9.4±0.5 degrees angstroms, at about 5.6±0.5 degreesangstroms, at about 5.0±0.5 degrees angstroms, at about 4.7±0.5 degreesangstroms, at about 3.7±0.5 degrees angstroms, at about 3.4±0.5 degreesangstroms, and at about 3.3±0.5 degrees angstroms.